Interleukin (IL)-6 is a pleiotropic cytokine involved in the differentiation and proliferation of hematopoietic cells. Hepatocytes respond to IL-6 with the synthesis and secretion of acute-phase proteins. In addition, IL-6 plays a role as a migration factor in vivo. In the present paper, we studied the potential of IL-6 to mediate migration of human primary T cells and T cell-derived cell lines. IL-6 was found to induce migration only in the presence of extracellular matrix, suggesting a cross-talk between the IL-6- and integrin signal transduction pathways. Furthermore, an IL-6 gradient is required for chemotactic migration. This activity is not due to the release of secondary chemotactic activities, but is a direct response to IL-6. T cell migration could also be observed in response to IL-11, but no migration was found after stimulation with leukemia inhibitory factor or oncostatin M, although these cytokines signal through gp130-containing receptor complexes. Finally, we present evidence that activation of the mitogen-activated protein kinase (MAPK) cascade, the phosphatidylinositol 3-kinase as well as the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is crucial for IL-6-induced migration. Selective activation of the JAK/STAT or the MAPK cascade by mutated receptor proteins shows a crucial role of IL-6-initiated SH2 domain-containing tyrosine phosphatase 2/MAPK activity for migration.